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Information on EC 3.2.2.29 - thymine-DNA glycosylase
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3.2.2.29 thymine-DNA glycosylaseIUBMB Comments
Thymine-DNA glycosylase is part of the DNA-repair machinery. Thymine removal is fastest when it is from a G/T mismatch with a 5'-flanking C/G pair. The glycosylase removes uracil from G/U, C/U, and T/U base pairs faster than it removes thymine from G/T .
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Word Map
- 3.2.2.29
-
demethylation
- 5-methylcytosine
- cytosine
-
deamination
- glycosylases
- 5-carboxylcytosine
- mispairs
- 5-formylcytosine
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5-hydroxymethylcytosine
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ten-eleven
-
excises
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uracil-dna
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abasic
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methyl-cpg
- 3,n4-ethenocytosine
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tdg-mediated
- 5-hydroxymethyluracil
- sumo-1
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base-excision
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methyl-cpg-binding
- medicine
The expected taxonomic range for this enzyme is: Archaea, Eukaryota
Reaction Schemes
Hydrolyses mismatched double-stranded DNA and polynucleotides, releasing free thymine.
Synonyms
thymine dna glycosylase, thymine-dna glycosylase, mismatch-specific thymine-dna glycosylase, pa-mig, g/t glycosylase, thymine dna-glycosylase, uracil/thymine dna glycosylase, mismatch-specific thymine-dna n-glycosylase, t:g mismatch-specific thymidine-dna glycosylase, 
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SYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
T/U mismatch DNA glycosylase
TDG
thymine DNA glycosylase
thymine DNA-glycosylase
thymine-DNA glycosylase
additional information
TDG
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TDG
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thymine DNA glycosylase
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thymine DNA glycosylase
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additional information
the enzyme belongs to the uracil-DNA glycosylase family
additional information
the enzyme is a member of the uracil DNA glycosylase, UDG, superfamily
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REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
Hydrolyses mismatched double-stranded DNA and polynucleotides, releasing free thymine.
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SYSTEMATIC NAME
IUBMB Comments
thymine-DNA deoxyribohydrolase (thymine-releasing)
Thymine-DNA glycosylase is part of the DNA-repair machinery. Thymine removal is fastest when it is from a G/T mismatch with a 5'-flanking C/G pair. The glycosylase removes uracil from G/U, C/U, and T/U base pairs faster than it removes thymine from G/T [3].
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CAS REGISTRY NUMBER
COMMENTARY
149565-68-4
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SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
3,N4-ethenocytosine-mismatched double-stranded DNA + H2O
3,N4-ethenocytosine + double-stranded DNA with abasic site
5-bromocytosine-mismatched double-stranded DNA + H2O
5-bromouracil + double-stranded DNA with abasic site
hTDG readily excises cytosine analogues with improved leaving ability, including 5-fluorocytosine, 5-bromocytosine, and 5-hydroxycytosine, indicating that cytosine has access to the active site. hTDG specificity depends on N-glycosidic bond stability, and the discrimination against cytosine is due largely to its very poor leaving ability rather than its exclusion from the active site
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-
?
5-bromouracil-mismatched double-stranded DNA + H2O
5-bromouracil + double-stranded DNA with abasic site
5-carboxylcytosine mismatched double-stranded DNA + H2O
5-carboxylcytosine + double-stranded DNA with abasic site
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?
5-carboxylcytosine-mismatched double-stranded DNA + H2O
5-carboxylcytosine + double-stranded DNA with abasic site
5-chlorouracil-mismatched double-stranded DNA + H2O
5-chlorouracil + double-stranded DNA with abasic site
5-fluorocytosine-mismatched double-stranded DNA + H2O
5-fluorocytosine + double-stranded DNA with abasic site
hTDG readily excises cytosine analogues with improved leaving ability, including 5-fluorocytosine, 5-bromocytosine, and 5-hydroxycytosine, indicating that cytosine has access to the active site. hTDG specificity depends on N-glycosidic bond stability, and the discrimination against cytosine is due largely to its very poor leaving ability rather than its exclusion from the active site
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?
5-fluorouracil-mismatched double-stranded DNA + H2O
5-fluorouracil + double-stranded DNA with abasic site
5-formylcytosine mismatched double-stranded DNA + H2O
5-formylcytosine + double-stranded DNA with abasic site
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?
5-formylcytosine-mismatched double-stranded DNA + H2O
5-formylcytosine + double-stranded DNA with abasic site
5-hydroxcytosine-mismatched double-stranded DNA + H2O
5-hydroxycytosine + double-stranded DNA with abasic site
hTDG readily excises cytosine analogues with improved leaving ability, including 5-fluorocytosine, 5-bromocytosine, and 5-hydroxycytosine, indicating that cytosine has access to the active site. hTDG specificity depends on N-glycosidic bond stability, and the discrimination against cytosine is due largely to its very poor leaving ability rather than its exclusion from the active site
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?
5-hydroxymethyluracil-mismatched double-stranded DNA + H2O
5-hydroxymethyluracil + double-stranded DNA with abasic site
5-hydroxymethyluridine-mismatched double-stranded DNA + H2O
5-hydroxymethyluridine + double-stranded DNA with abasic site
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?
5-hydroxyuracil-mismatched double-stranded DNA + H2O
5-hydroxyuracil + double-stranded DNA with abasic site
removes 5-hydroxyuracil from G/5-hydroxyuracil mismatches
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-
?
5-methylcytosine-mismatched double-stranded DNA + H2O
5-methylcytosine + double-stranded DNA with abasic site
8-(hydroxymethyl)-3,N4-ethenocytosine-mismatched double-stranded DNA + H2O
8-(hydroxymethyl)-3,N4-ethenocytosine + double-stranded DNA with abasic site
TDG is able to excise the 8-(hydroxymethyl)-3,N4-ethenocytosine from DNA. TDG activity displays a marked preference of guanine opposite to 8-(hydroxymethyl)-3,N4-ethenocytosine over any other bases. TDG does not show any detectable activity toward 3,N4-ethanocytosine when placed in various neighboring sequences, including the 5'-CpG site
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?
cytosine-mismatched double-stranded DNA + H2O
cytosine + double-stranded DNA with abasic site
paired with guanine
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?
double-stranded DNA + H2O
?
thymine-DNA glycosylase has a strong sequence preference for CpG sites in the excision of both thymine and ethenocytosine. This suggests a main role of thymine-DNA glycosylase in vivo is the removal of thymine produced by deamination of 5-methylcytosine at CpG sites
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?
thymine glycol -mismatched double-stranded DNA + H2O
thymine glycol + double-stranded DNA with abasic site
thymine glycol from G/thymine glycol mismatches
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?
thymine glycol-mismatched double-stranded DNA + H2O
thymine glycol + double-stranded DNA with abasic site
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oligonucleotides with thymine glycol incorporated into different sequence contexts and paired with adenine or guanine. TDG and methyl-CpG-binding protein 4 can remove thymine glycol when present opposite guanine but not when paired with adenine. The efficiency of these enzymes for removal of thymine glycol is about half of that for removal of thymine in the same sequence context. The two proteins may have evolved to act specifically on DNA mismatches produced by deamination and by oxidation-coupled deamination of 5-methylcytosine. This repair pathway contributes to mutation avoidance at methylated CpG dinucleotides
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?
thymine-guanine mismatched double-stranded DNA + H2O
thymine + double-stranded DNA with abasic site
thymine-guanine-mismatched double-stranded DNA + H2O
thymine + double-stranded DNA with abasic site
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?
thymine-mismatched double-stranded DNA + H2O
thymine + double-stranded DNA with abasic site
uracil-mismatched double-stranded DNA + H2O
uracil + double-stranded DNA with abasic site
uridine-mismatched double-stranded DNA + H2O
uridine + double-stranded DNA with abasic site
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?
3,N4-ethenocytosine-mismatched double-stranded DNA + H2O
3,N4-ethenocytosine + double-stranded DNA with abasic site
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?
3,N4-ethenocytosine-mismatched double-stranded DNA + H2O
3,N4-ethenocytosine + double-stranded DNA with abasic site
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?
3,N4-ethenocytosine-mismatched double-stranded DNA + H2O
3,N4-ethenocytosine + double-stranded DNA with abasic site
3,N4-ethenocytosine is recognized and efficiently excised by hTDG. The enzyme may be responsible for the repair of this mutagenic lesion in vivo and be important contributors to genetic stability
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?
3,N4-ethenocytosine-mismatched double-stranded DNA + H2O
3,N4-ethenocytosine + double-stranded DNA with abasic site
3,N4-ethenocytosine is recognized and efficiently excised from the 3,N4-ethenocytosine/G duplex oligonucleotide, when this residue is situated opposite to G. 26.5% of the activity measured with 3,N4-ethenocytosine mismatches is observed with 3,N4-ethenocytosine/A mismatches, 71% with 3,N4-ethenocytosine/A mismatches
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?
3,N4-ethenocytosine-mismatched double-stranded DNA + H2O
3,N4-ethenocytosine + double-stranded DNA with abasic site
ethenocytosine base-paired with guanine within a CpG site (i.e. CpG-ethenocytosine-DNA) is by far the best substrate. The next best substrates are DNA duplexes containing TpG/ethenocytosine, GpG/ethenocytosine, and CpG/T. The worst substrates are DNA duplexes containing ApG/ethenocytosine and TpG/T. DNA containing ethenocytosine is bound much more tightly than DNA containing a G/T mismatch
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?
3,N4-ethenocytosine-mismatched double-stranded DNA + H2O
3,N4-ethenocytosine + double-stranded DNA with abasic site
removes 3,N4-ethenocytosine from G/3,N4-ethenocytosine and A/3,N4-ethenocytosine mismatches
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?
5-bromouracil-mismatched double-stranded DNA + H2O
5-bromouracil + double-stranded DNA with abasic site
potential role played by human TDG in the cytotoxic effects of 5-chlorouracil and 5-bromouracil incorporation into DNA, which can occur under inflammatory conditions
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?
5-bromouracil-mismatched double-stranded DNA + H2O
5-bromouracil + double-stranded DNA with abasic site
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in addition to uracil and thymine, the protein can also remove 5-bromouracil from mispairs with guanine
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?
5-bromouracil-mismatched double-stranded DNA + H2O
5-bromouracil + double-stranded DNA with abasic site
paired with guanine
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?
5-bromouracil-mismatched double-stranded DNA + H2O
5-bromouracil + double-stranded DNA with abasic site
removes 5-bromouracil from G/5-bromouracil mismatches
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?
5-carboxylcytosine-mismatched double-stranded DNA + H2O
5-carboxylcytosine + double-stranded DNA with abasic site
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?
5-carboxylcytosine-mismatched double-stranded DNA + H2O
5-carboxylcytosine + double-stranded DNA with abasic site
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?
5-carboxylcytosine-mismatched double-stranded DNA + H2O
5-carboxylcytosine + double-stranded DNA with abasic site
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?
5-chlorouracil-mismatched double-stranded DNA + H2O
5-chlorouracil + double-stranded DNA with abasic site
potential role played by human TDG in the cytotoxic effects of 5-chlorouracil and 5-bromouracil incorporation into DNA, which can occur under inflammatory conditions
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?
5-chlorouracil-mismatched double-stranded DNA + H2O
5-chlorouracil + double-stranded DNA with abasic site
hTDG removes 5-chlorouracil 572fold faster than thymine
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?
5-chlorouracil-mismatched double-stranded DNA + H2O
5-chlorouracil + double-stranded DNA with abasic site
removes a variety of damaged bases (X) with a preference for lesions in a CpG/X context. The maximal activity for G/X substrates depends significantly on the 5' base pair. The maximal activity decreases by 6fold, 11fold, and 82fold for TpG/5-chlorouracil, GpG/5-chlorouracil, and ApG/5-chlorouracil, respectively, as compared with CpG/5-chlorouracil. Human TDG activity is reduced 102.3104.3fold for A/X relative to G/X pairs and reduced further for A/X pairs with a 5' pair other than C/G. The effect of altering the 5' pair and/or the opposing base (G/X versus A/X) is greater for substrates that are larger (bromodeoxyuridine, dT) or have a more stable N-glycosidic bond (such as dT). The largest CpG context effects are observed for the excision of thymine
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?
5-fluorouracil-mismatched double-stranded DNA + H2O
5-fluorouracil + double-stranded DNA with abasic site
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?
5-fluorouracil-mismatched double-stranded DNA + H2O
5-fluorouracil + double-stranded DNA with abasic site
hTDG removes 5-fluorouracil 78fold faster than uracil
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?
5-fluorouracil-mismatched double-stranded DNA + H2O
5-fluorouracil + double-stranded DNA with abasic site
paired with guanine
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?
5-fluorouracil-mismatched double-stranded DNA + H2O
5-fluorouracil + double-stranded DNA with abasic site
removes 5-fluorouracil from G/5-fluorouracil and A/5-fluorouracil mismatches
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?
5-fluorouracil-mismatched double-stranded DNA + H2O
5-fluorouracil + double-stranded DNA with abasic site
the activity for G/5-fluorouracil, G/5-chlorouracil, and G/5-bromouracil, with any 5'-flanking pair, meets and in most cases significantly exceeds the CpG/T activity. Human TDG activity is reduced 102.3104.3fold for A/X relative to G/X pairs and reduced further for A/X pairs with a 5' pair other than C/G. The effect of altering the 5' pair and/or the opposing base (G/X versus A/X) is greater for substrates that are larger (bromodeoxyuridine, dT) or have a more stable N-glycosidic bond (such as dT). The largest CpG context effects are observed for the excision of thymine
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?
5-formylcytosine-mismatched double-stranded DNA + H2O
5-formylcytosine + double-stranded DNA with abasic site
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?
5-formylcytosine-mismatched double-stranded DNA + H2O
5-formylcytosine + double-stranded DNA with abasic site
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?
5-formylcytosine-mismatched double-stranded DNA + H2O
5-formylcytosine + double-stranded DNA with abasic site
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?
5-hydroxymethyluracil-mismatched double-stranded DNA + H2O
5-hydroxymethyluracil + double-stranded DNA with abasic site
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?
5-hydroxymethyluracil-mismatched double-stranded DNA + H2O
5-hydroxymethyluracil + double-stranded DNA with abasic site
paired with guanine
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?
5-hydroxymethyluracil-mismatched double-stranded DNA + H2O
5-hydroxymethyluracil + double-stranded DNA with abasic site
removes 5-hydroxymethyluracil from G/5-hydroxymethyluracil mismatches
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?
5-methylcytosine-mismatched double-stranded DNA + H2O
5-methylcytosine + double-stranded DNA with abasic site
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?
5-methylcytosine-mismatched double-stranded DNA + H2O
5-methylcytosine + double-stranded DNA with abasic site
paired with guanine
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?
thymine-guanine mismatched double-stranded DNA + H2O
thymine + double-stranded DNA with abasic site
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?
thymine-guanine mismatched double-stranded DNA + H2O
thymine + double-stranded DNA with abasic site
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thiol-modified hairpin probe DNA with 5' overhangs and one mismatched base pair of guanine:thymine in the stem part
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?
thymine-mismatched double-stranded DNA + H2O
thymine + double-stranded DNA with abasic site
G-T mismatch is only a poor substrate for Thd1p
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?
thymine-mismatched double-stranded DNA + H2O
thymine + double-stranded DNA with abasic site
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?
thymine-mismatched double-stranded DNA + H2O
thymine + double-stranded DNA with abasic site
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?
thymine-mismatched double-stranded DNA + H2O
thymine + double-stranded DNA with abasic site
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?
thymine-mismatched double-stranded DNA + H2O
thymine + double-stranded DNA with abasic site
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?
thymine-mismatched double-stranded DNA + H2O
thymine + double-stranded DNA with abasic site
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?
thymine-mismatched double-stranded DNA + H2O
thymine + double-stranded DNA with abasic site
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?
thymine-mismatched double-stranded DNA + H2O
thymine + double-stranded DNA with abasic site
about 23% of mutations in hereditary human diseases and 24% of mutations in p53 in human cancers are G to A transitions at sites of cytosine methylation suggesting that these sites are either foci for DNA damage, or foci for damage that is poorly repaired. Thymine produced at these sites by the hydrolytic deamination of 5-methylcytosine is removed by thymine-DNA glycosylase. Thymine-DNA glycosylase also removes 3,N4-ethenocytosine and uracil from DNA. The action of this enzyme is limited by its very low kcat and by tight binding to the apurinic site produced when the thymine is removed. These properties of the enzyme suggest that the inefficiency of the base excision repair pathway that it initiates may be the underlying cause of the prevalence of these mutations
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?
thymine-mismatched double-stranded DNA + H2O
thymine + double-stranded DNA with abasic site
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oligonucleotides with thymine glycol incorporated into different sequence contexts and paired with adenine or guanine. TDG and methyl-CpG-binding protein 4 can remove thymine glycol when present opposite guanine but not when paired with adenine. The efficiency of these enzymes for removal of thymine glycol is about half of that for removal of thymine in the same sequence context. The two proteins may have evolved to act specifically on DNA mismatches produced by deamination and by oxidation-coupled deamination of 5-methylcytosine. This repair pathway contributes to mutation avoidance at methylated CpG dinucleotides
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?
thymine-mismatched double-stranded DNA + H2O
thymine + double-stranded DNA with abasic site
the enzyme initiates the repair process by excising the mispaired thymine from the heteroduplex to generate an apyrimidinic site
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?
thymine-mismatched double-stranded DNA + H2O
thymine + double-stranded DNA with abasic site
the human enzyme excises thymine and uracil from G-T and G-U mismatches, respectively, and is therefore proposed to play a central role in the cellular defense against genetic mutation through spontaneous deamination of 5-methylcytosine and cytosine
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?
thymine-mismatched double-stranded DNA + H2O
thymine + double-stranded DNA with abasic site
45-bp DNA heteroduplexes that bear single G/T, O6-methyguanine, 2,6-diaminopurine/T, 2-amino-6-(methylamino)-purine/T, 2-aminopurine/T, and G/O4-methylthymine mispairs. The bases 5' to the poorly matched G are altered in selected G/T substrates to yield mispairs in four different contexts, ApG, CpG, GpG, and TpG. The recombinant thymine glycosylase is incubated with the 45-bp DNA substrates, each labeled at the 5'-terminus of the strand containing the mismatched T. The rate of incision is greatest with DNA containing the G/T mispair followed by the DNA containing the O6-methylguanine/T mispair and the DNA with the 2-amino-6-(methylamino)purine/T mispair. The extent of reaction is 90%, 40%, and 20% respectively. DNA substrates containing 2,6-diaminopurine/T, 2-aminopurine/T, and G/O4-methylthymine mispairs are not incised. The amount of incision of the 45-bp DNA substrates containing G/T mispairs in the CpG context is 3-12fold greater than in the TpG, GpG, and ApG contexts
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?
thymine-mismatched double-stranded DNA + H2O
thymine + double-stranded DNA with abasic site
cleaves thymine from mutagenic G/T mispairs. Recognizes many additional lesions, and has a strong preference for nucleobases paired with guanine rather than adenine. hTDG avoids cytosine, despite the million-fold excess of normal G/C pairs over G/T mispairs
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?
thymine-mismatched double-stranded DNA + H2O
thymine + double-stranded DNA with abasic site
each molecule of thymine DNA glycosylase removes only one molecule of thymine from DNA containing a G/T mismatch because it binds tightly to the apurinic DNA site left after removal of thymine. The 5'-flanking base pair to G/T mismatches influences the rate of removal of thymine. Thymine DNA glycosylase can also remove thymine from mismatches with S6-methylthioguanine, but, unlike G/T mismatches, a 5'-C-G does not have a striking effect on the rate. Thymine removal is fastest when it is from a G/T mismatch with a 5'-flanking C/G pair, suggesting that the rapid reaction of this substrate involves contacts between the enzyme and oxygen 6 or the N-1 hydrogen of the mismatched guanine as well as the 5'-flanking C/G pair
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?
thymine-mismatched double-stranded DNA + H2O
thymine + double-stranded DNA with abasic site
ethenocytosine base-paired with guanine within a CpG site (i.e. CpG-ethenocytosine-DNA) is by far the best substrate. The next best substrates are DNA duplexes containing TpG/ethenocytosine, GpG/ethenocytosine, and CpG/T. The worst substrates are DNA duplexes containing ApG/ethenocytosine and TpG/T. DNA containing ethenocytosine is bound much more tightly than DNA containing a G/T mismatch
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?
thymine-mismatched double-stranded DNA + H2O
thymine + double-stranded DNA with abasic site
excision of thymine from T/G mismatches
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?
thymine-mismatched double-stranded DNA + H2O
thymine + double-stranded DNA with abasic site
-
in addition to uracil and thymine, the protein can also remove 5-bromouracil from mispairs with guanine
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?
thymine-mismatched double-stranded DNA + H2O
thymine + double-stranded DNA with abasic site
paired with guanine
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?
thymine-mismatched double-stranded DNA + H2O
thymine + double-stranded DNA with abasic site
removes thymine from G/T mismatches
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?
thymine-mismatched double-stranded DNA + H2O
thymine + double-stranded DNA with abasic site
the enzyme is capable for hydrolyzing the carbon-nitrogen bond between the sugar-phosphate backbone of the DNA and a mispaired thymine. In addition to G/T, the enzyme can remove thymine also from C/T and T/T mispairs in the order of decreasing efficiency: G/T, C/T, T/T. It has no detectable endonucleolytic activity on apyrimidinic sites and does not catalyze the removal of thymine from A/T pairs or from single-stranded DNA
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?
thymine-mismatched double-stranded DNA + H2O
thymine + double-stranded DNA with abasic site
the recombinant enzyme shows a significant preference for G/T mispairs in a CpG context. The enzyme is also capable of processing mismatches between thymine and 6-O-methylguanine, whereby it generates an apyrimidinic site opposite the modified guanine. TDG preferentially addresses 6-O-methyl G/T mispairs when the neighboring base 5' to the 6-O-methyl G is a C rather than a G. TDG is the only enzyme present in the HeLa nuclear extracts capable of processing G/T mispairs in oligonucleotide substrate
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?
thymine-mismatched double-stranded DNA + H2O
thymine + double-stranded DNA with abasic site
thymine DNA glycosylase excises thymine from G/T mispairs. Human TDG activity is reduced 102.3104.3fold for A/X relative to G/X pairs and reduced further for A/X pairs with a 5' pair other than C/G. The effect of altering the 5' pair and/or the opposing base (G/X versus A/X) is greater for substrates that are larger (bromodeoxyuridine, dT) or have a more stable N-glycosidic bond (such as dT). The largest CpG context effects are observed for the excision of thymine
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-
?
thymine-mismatched double-stranded DNA + H2O
thymine + double-stranded DNA with abasic site
thymine-DNA glycosylase is more active on mismatches containing uracil than on mismatches containing thymine
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?
thymine-mismatched double-stranded DNA + H2O
thymine + double-stranded DNA with abasic site
-
the enzyme is capable of removing thymine that has mispaired with 3,N4-ethenocytosine, butanone-ethenocytosine, butanone-ethenoguanine, heptanone-ethenocytosine, or heptanone-ethenoguanine in vitro
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?
thymine-mismatched double-stranded DNA + H2O
thymine + double-stranded DNA with abasic site
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?
thymine-mismatched double-stranded DNA + H2O
thymine + double-stranded DNA with abasic site
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DNA repair enzyme which corrects G/T mismatches that result from the hydrolytic deamination of 5-methyl cytosines
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?
thymine-mismatched double-stranded DNA + H2O
thymine + double-stranded DNA with abasic site
-
DNA containing a single G/T mismatch
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?
thymine-mismatched double-stranded DNA + H2O
thymine + double-stranded DNA with abasic site
Q9P9L6
removes thymine from T/G mismatches
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-
?
uracil-mismatched double-stranded DNA + H2O
uracil + double-stranded DNA with abasic site
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?
uracil-mismatched double-stranded DNA + H2O
uracil + double-stranded DNA with abasic site
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?
uracil-mismatched double-stranded DNA + H2O
uracil + double-stranded DNA with abasic site
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-
?
uracil-mismatched double-stranded DNA + H2O
uracil + double-stranded DNA with abasic site
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-
?
uracil-mismatched double-stranded DNA + H2O
uracil + double-stranded DNA with abasic site
-
biological role in vivo may also include the correction of a subset of G/U mispairs inefficiently removed by the more abundant ubiquitous uracil glycosylases
-
-
?
uracil-mismatched double-stranded DNA + H2O
uracil + double-stranded DNA with abasic site
the human enzyme excises thymine and uracil from G-T and G-U mismatches, respectively, and is therefore proposed to play a central role in the cellular defense against genetic mutation through spontaneous deamination of 5-methylcytosine and cytosine
-
-
?
uracil-mismatched double-stranded DNA + H2O
uracil + double-stranded DNA with abasic site
thymine DNA glycosylase may play a backup role to the more efficient general uracil DNA glycosylase
-
-
?
uracil-mismatched double-stranded DNA + H2O
uracil + double-stranded DNA with abasic site
excision of uracil from U/G mismatches
-
-
?
uracil-mismatched double-stranded DNA + H2O
uracil + double-stranded DNA with abasic site
-
in addition to uracil and thymine, the protein can also remove 5-bromouracil from mispairs with guanine
-
-
?
uracil-mismatched double-stranded DNA + H2O
uracil + double-stranded DNA with abasic site
removes uracil from G/U mismatches
-
-
?
uracil-mismatched double-stranded DNA + H2O
uracil + double-stranded DNA with abasic site
the glycosylase removes uracil from G/U, C/U, and T/U base pairs faster than it removes thymine from G/T. It can even remove uracil from A/U base pairs, although at a very much lower rate
-
-
?
uracil-mismatched double-stranded DNA + H2O
uracil + double-stranded DNA with abasic site
thymine-DNA glycosylase is more active on mismatches containing uracil than on mismatches containing thymine
-
-
?
uracil-mismatched double-stranded DNA + H2O
uracil + double-stranded DNA with abasic site
Q9P9L6
removes uracil from G/U mismatches, U/7,8-dihydro-oxoguanine and T/7,8-dihydro-oxoguanine mismatches
-
-
?
additional information
?
-
-
excision of T:G mismatches in oligonucleotide substrates. Aeropyrum pernix TDG also has a relatively weak DNA glycosylase activity on uracil base, with the following descending order: U/C - U/G = U/T = U/U = U/I = U/AP = U/- - U/A. Additional mismatch located at 3' of T/G have less inhibitory effect on the thymine removal than that located at 5' of T/G. Two additional mismatches located at each side of T/G completely inhibit the excision of thymine
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-
?
additional information
?
-
the enzyme shows a broad and species-specific substrate spectrum, substrate binding structure, overview. The common most efficiently processed substrates of all are uracil and 3,N4-ethenocytosine opposite guanine and 5-fluorouracil in any double-stranded DNA context, the enzyme is able to hydrolyze a non-damaged 5'-methylcytosine opposite G, and the double strand and mismatch dependency of the enzymes varies with the substrate
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-
?
additional information
?
-
-
the enzyme shows a broad and species-specific substrate spectrum, substrate binding structure, overview. The common most efficiently processed substrates of all are uracil and 3,N4-ethenocytosine opposite guanine and 5-fluorouracil in any double-stranded DNA context, the enzyme is able to hydrolyze a non-damaged 5'-methylcytosine opposite G, and the double strand and mismatch dependency of the enzymes varies with the substrate
-
-
?
additional information
?
-
inactivation of TDG significantly increases resistance of human cancer cells towards 5-fluorouracil. Excision of DNA-incorporated 5-fluorouracil by TDG generates persistent DNA strand breaks, delays S-phase progression, and activates DNA damage signaling. The repair of 5-fluorouracilinduced DNA strand breaks is more efficient in the absence of TDG. Excision of 5-fluorouracil by TDG (but not by uracil DNA glycosylases (UNG2 and SMUG1)) prevents efficient downstream processing of the repair intermediate, thereby mediating DNA-directed cytotoxicity
-
-
?
additional information
?
-
-
inactivation of TDG significantly increases resistance of human cancer cells towards 5-fluorouracil. Excision of DNA-incorporated 5-fluorouracil by TDG generates persistent DNA strand breaks, delays S-phase progression, and activates DNA damage signaling. The repair of 5-fluorouracilinduced DNA strand breaks is more efficient in the absence of TDG. Excision of 5-fluorouracil by TDG (but not by uracil DNA glycosylases (UNG2 and SMUG1)) prevents efficient downstream processing of the repair intermediate, thereby mediating DNA-directed cytotoxicity
-
-
?
additional information
?
-
uncertainty about the biological function of TDG. TDG is a DNA glycosylase involved in the repair of damaged DNA bases. Judged from its interactions with other proteins, it is a co-regulator of gene expression
-
-
?
additional information
?
-
-
DNA repair enzyme specific for G/T mismatches. TDG acts as a transcriptional coactivator, modulates the biological function of p53 family proteins without member specificity
-
-
?
additional information
?
-
human TDG removes the substrate pyrimidines 5-fluorouracil, 5-hydroxymethyluracil, 5-bromouracil, epsilonC and thymine paired with guanine with high relative efficiencies, substrate spectrum and substrate binding structure, overview
-
-
?
additional information
?
-
-
human TDG removes the substrate pyrimidines 5-fluorouracil, 5-hydroxymethyluracil, 5-bromouracil, epsilonC and thymine paired with guanine with high relative efficiencies, substrate spectrum and substrate binding structure, overview
-
-
?
additional information
?
-
TDG interacts with, but also is modified by SUMO-1 and SUMO-3, SUMOylation enhances G-U processing while abolishing G-T processing, mechanism, overview. SUMO modification in the C-terminus converts TDG to an enzyme with Mug-like properties, as does the deletion of the N-terminus, overview
-
-
?
additional information
?
-
-
TDG has a strong preference for uracil over thymine. TDG is an intriguing protein that, similar to SMUG1, has a low turnover number and strong binding to AP sites. The binding of the glycosylase to the AP site inhibits cleavage by the downstream AP endonuclease
-
-
?
additional information
?
-
TDG promotes genomic integrity by excising thymine from mutagenic G:T mismatches arising by deamination of 5-methylcytosine, and follow-on base excision repair enzymes restore a G:C pair. TDG cleaves the N-glycosylic bond of dT and some other nucleotides, including 5-substituted 2'-deoxyuridine analogues, once they are flipped from the helix into its active site. All of the DNA glycosylases employ nucleotide flipping to extrude the target nucleotide from the helix and gain access to the damaged base and the scissile N-glycosylic bond
-
-
?
additional information
?
-
-
TDG promotes genomic integrity by excising thymine from mutagenic G:T mismatches arising by deamination of 5-methylcytosine, and follow-on base excision repair enzymes restore a G:C pair. TDG cleaves the N-glycosylic bond of dT and some other nucleotides, including 5-substituted 2'-deoxyuridine analogues, once they are flipped from the helix into its active site. All of the DNA glycosylases employ nucleotide flipping to extrude the target nucleotide from the helix and gain access to the damaged base and the scissile N-glycosylic bond
-
-
?
additional information
?
-
-
thymine DNA glycosylase and methyl binding domain protein 4 act on G:IU, i.e. iododeoxyuridine, but not A:IU, mispairs and are functionally complementary to each other
-
-
?
additional information
?
-
-
IUdR is a thymidine analogue which has been used in the clinic as a radiosensitizer. Following active cell membrane transport, IUdR is sequentially phosphorylated to IdUTP which competes with thymidine, TdR, for DNA incorporation. G:IU mispair is a substrate for thymidine DNA glycosylase
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-
?
additional information
?
-
-
TDG has a strong preference for uracil over thymine, it also has a strong preference for U:G mismatches
-
-
?
additional information
?
-
TDG cleaves the N-glycosylic bond of dT and some other nucleotides, including 5-substituted 2'-deoxyuridine analogues, once they are flipped from the helix into its active site. Residue Asn140, in motif 138GINPG142, is implicated in the chemical step, does not contribute substantially to substrate binding, and residue Arg275 in nucleotide flipping, Arg275 penetrates the DNA minor groove, filling the void created by nucleotide flipping, active site structure, overview. DNA glycosylases employ nucleotide flipping to extrude the target nucleotide from the helix and gain access to the damaged base and the scissile N-glycosylic bond. The enzyme can also remove 5-halogenated uracils, 5-fluorouracil, 5-chlorouracil, 5-bromouracil, and 5-iodouracil, many other 5-substituted uracils, N4-ethenocytosine, hypoxanthine, and other damaged bases, but not with substrate analogueG:2'-deoxy-2'-fluoroarabinouridine, substrate binding structure and kinetics, overview
-
-
?
additional information
?
-
-
TDG cleaves the N-glycosylic bond of dT and some other nucleotides, including 5-substituted 2'-deoxyuridine analogues, once they are flipped from the helix into its active site. Residue Asn140, in motif 138GINPG142, is implicated in the chemical step, does not contribute substantially to substrate binding, and residue Arg275 in nucleotide flipping, Arg275 penetrates the DNA minor groove, filling the void created by nucleotide flipping, active site structure, overview. DNA glycosylases employ nucleotide flipping to extrude the target nucleotide from the helix and gain access to the damaged base and the scissile N-glycosylic bond. The enzyme can also remove 5-halogenated uracils, 5-fluorouracil, 5-chlorouracil, 5-bromouracil, and 5-iodouracil, many other 5-substituted uracils, N4-ethenocytosine, hypoxanthine, and other damaged bases, but not with substrate analogueG:2'-deoxy-2'-fluoroarabinouridine, substrate binding structure and kinetics, overview
-
-
?
additional information
?
-
the enzyme has negligible affinity for isolated nucleobases
-
-
?
additional information
?
-
the enzyme is degraded in response to DNA damage. UV-induced enzyme degradation is mediated by CRL4(CDT2) E3 ligase which ubiquitinates the enzyme
-
-
?
additional information
?
-
the enzyme removes thymine from mutagenic G-T mispairs caused by 5-methylcytosine deamination and other lesions including uracil and 5-hydroxymethyluracil. In DNA demethylation, the enzyme excises 5-formylcytosine and 5-carboxylcytosine
-
-
?
additional information
?
-
-
DNA methyltransferase Dnmt3a interacts with TDG. Both the PWWP domain and the catalytic domain of Dnmt3a are able to mediate the interaction with TDG at its N-terminus. The interaction affects the enzymatic activity of both proteins: Dnmt3a positively regulates the glycosylase activity of TDG, while TDG inhibits the methylation activity of Dnmt3a in vitro. Mechanistic link between DNA repair and remethylation at sites affected by methylcytosine deamination
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-
?
additional information
?
-
-
TDG can inhibit expression of smooth muscle-specific genes, at least in part, through disrupting serum response factor/myocardin interactions. The glycosylase activity of TDG is not required for its inhibitory effects on myocardin function. Role for the repair enzyme TDG as a repressor of smooth muscle differentiation via competing with serum response factor for binding to myocardin
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-
?
additional information
?
-
-
TDG has a strong preference for uracil over thymine. TDG is an intriguing protein that, similar to SMUG1, has a low turnover number and strong binding to AP sites. The binding of the glycosylase to the AP site inhibits cleavage by the downstream AP endonuclease
-
-
?
additional information
?
-
-
TDG has a strong preference for uracil over thymine, it also has a strong preference for U:G mismatches
-
-
?
additional information
?
-
-
TDG performs DNA processing of G:T mispairs, base excision from oligonucleotides containing a single G:U or G:T mispair
-
-
?
additional information
?
-
-
the enzyme repairs a G:T mismatch to G:C, development of a spectrometric assay system for specific and quantitative measurement of intracellular DNA glycosylase activity, overview
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?
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NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
3,N4-ethenocytosine-mismatched double-stranded DNA + H2O
3,N4-ethenocytosine + double-stranded DNA with abasic site
3,N4-ethenocytosine is recognized and efficiently excised by hTDG. The enzyme may be responsible for the repair of this mutagenic lesion in vivo and be important contributors to genetic stability
-
-
?
5-bromouracil-mismatched double-stranded DNA + H2O
5-bromouracil + double-stranded DNA with abasic site
potential role played by human TDG in the cytotoxic effects of 5-chlorouracil and 5-bromouracil incorporation into DNA, which can occur under inflammatory conditions
-
-
?
5-carboxylcytosine mismatched double-stranded DNA + H2O
5-carboxylcytosine + double-stranded DNA with abasic site
-
-
-
?
5-carboxylcytosine-mismatched double-stranded DNA + H2O
5-carboxylcytosine + double-stranded DNA with abasic site
5-chlorouracil-mismatched double-stranded DNA + H2O
5-chlorouracil + double-stranded DNA with abasic site
potential role played by human TDG in the cytotoxic effects of 5-chlorouracil and 5-bromouracil incorporation into DNA, which can occur under inflammatory conditions
-
-
?
5-formylcytosine-mismatched double-stranded DNA + H2O
5-formylcytosine + double-stranded DNA with abasic site
5-hydroxymethyluracil-mismatched double-stranded DNA + H2O
5-hydroxymethyluracil + double-stranded DNA with abasic site
-
-
-
?
5-hydroxymethyluridine-mismatched double-stranded DNA + H2O
5-hydroxymethyluridine + double-stranded DNA with abasic site
-
-
-
?
double-stranded DNA + H2O
?
thymine-DNA glycosylase has a strong sequence preference for CpG sites in the excision of both thymine and ethenocytosine. This suggests a main role of thymine-DNA glycosylase in vivo is the removal of thymine produced by deamination of 5-methylcytosine at CpG sites
-
-
?
thymine glycol-mismatched double-stranded DNA + H2O
thymine glycol + double-stranded DNA with abasic site
-
oligonucleotides with thymine glycol incorporated into different sequence contexts and paired with adenine or guanine. TDG and methyl-CpG-binding protein 4 can remove thymine glycol when present opposite guanine but not when paired with adenine. The efficiency of these enzymes for removal of thymine glycol is about half of that for removal of thymine in the same sequence context. The two proteins may have evolved to act specifically on DNA mismatches produced by deamination and by oxidation-coupled deamination of 5-methylcytosine. This repair pathway contributes to mutation avoidance at methylated CpG dinucleotides
-
-
?
thymine-guanine mismatched double-stranded DNA + H2O
thymine + double-stranded DNA with abasic site
-
-
-
-
?
thymine-guanine-mismatched double-stranded DNA + H2O
thymine + double-stranded DNA with abasic site
-
-
-
?
thymine-mismatched double-stranded DNA + H2O
thymine + double-stranded DNA with abasic site
uridine-mismatched double-stranded DNA + H2O
uridine + double-stranded DNA with abasic site
-
-
-
?
5-carboxylcytosine-mismatched double-stranded DNA + H2O
5-carboxylcytosine + double-stranded DNA with abasic site
-
-
-
?
5-carboxylcytosine-mismatched double-stranded DNA + H2O
5-carboxylcytosine + double-stranded DNA with abasic site
-
-
-
-
?
5-carboxylcytosine-mismatched double-stranded DNA + H2O
5-carboxylcytosine + double-stranded DNA with abasic site
-
-
-
?
5-formylcytosine-mismatched double-stranded DNA + H2O
5-formylcytosine + double-stranded DNA with abasic site
-
-
-
?
5-formylcytosine-mismatched double-stranded DNA + H2O
5-formylcytosine + double-stranded DNA with abasic site
-
-
-
-
?
5-formylcytosine-mismatched double-stranded DNA + H2O
5-formylcytosine + double-stranded DNA with abasic site
-
-
-
?
thymine-mismatched double-stranded DNA + H2O
thymine + double-stranded DNA with abasic site
-
-
-
-
?
thymine-mismatched double-stranded DNA + H2O
thymine + double-stranded DNA with abasic site
-
-
-
?
thymine-mismatched double-stranded DNA + H2O
thymine + double-stranded DNA with abasic site
-
-
-
-
?
thymine-mismatched double-stranded DNA + H2O
thymine + double-stranded DNA with abasic site
-
-
-
?
thymine-mismatched double-stranded DNA + H2O
thymine + double-stranded DNA with abasic site
-
-
-
-
?
thymine-mismatched double-stranded DNA + H2O
thymine + double-stranded DNA with abasic site
-
-
-
?
thymine-mismatched double-stranded DNA + H2O
thymine + double-stranded DNA with abasic site
about 23% of mutations in hereditary human diseases and 24% of mutations in p53 in human cancers are G to A transitions at sites of cytosine methylation suggesting that these sites are either foci for DNA damage, or foci for damage that is poorly repaired. Thymine produced at these sites by the hydrolytic deamination of 5-methylcytosine is removed by thymine-DNA glycosylase. Thymine-DNA glycosylase also removes 3,N4-ethenocytosine and uracil from DNA. The action of this enzyme is limited by its very low kcat and by tight binding to the apurinic site produced when the thymine is removed. These properties of the enzyme suggest that the inefficiency of the base excision repair pathway that it initiates may be the underlying cause of the prevalence of these mutations
-
-
?
thymine-mismatched double-stranded DNA + H2O
thymine + double-stranded DNA with abasic site
-
oligonucleotides with thymine glycol incorporated into different sequence contexts and paired with adenine or guanine. TDG and methyl-CpG-binding protein 4 can remove thymine glycol when present opposite guanine but not when paired with adenine. The efficiency of these enzymes for removal of thymine glycol is about half of that for removal of thymine in the same sequence context. The two proteins may have evolved to act specifically on DNA mismatches produced by deamination and by oxidation-coupled deamination of 5-methylcytosine. This repair pathway contributes to mutation avoidance at methylated CpG dinucleotides
-
-
?
thymine-mismatched double-stranded DNA + H2O
thymine + double-stranded DNA with abasic site
the enzyme initiates the repair process by excising the mispaired thymine from the heteroduplex to generate an apyrimidinic site
-
-
?
thymine-mismatched double-stranded DNA + H2O
thymine + double-stranded DNA with abasic site
the human enzyme excises thymine and uracil from G-T and G-U mismatches, respectively, and is therefore proposed to play a central role in the cellular defense against genetic mutation through spontaneous deamination of 5-methylcytosine and cytosine
-
-
?
thymine-mismatched double-stranded DNA + H2O
thymine + double-stranded DNA with abasic site
-
-
-
-
?
thymine-mismatched double-stranded DNA + H2O
thymine + double-stranded DNA with abasic site
-
DNA repair enzyme which corrects G/T mismatches that result from the hydrolytic deamination of 5-methyl cytosines
-
-
?
uracil-mismatched double-stranded DNA + H2O
uracil + double-stranded DNA with abasic site
-
-
-
?
uracil-mismatched double-stranded DNA + H2O
uracil + double-stranded DNA with abasic site
-
-
-
?
uracil-mismatched double-stranded DNA + H2O
uracil + double-stranded DNA with abasic site
-
biological role in vivo may also include the correction of a subset of G/U mispairs inefficiently removed by the more abundant ubiquitous uracil glycosylases
-
-
?
uracil-mismatched double-stranded DNA + H2O
uracil + double-stranded DNA with abasic site
the human enzyme excises thymine and uracil from G-T and G-U mismatches, respectively, and is therefore proposed to play a central role in the cellular defense against genetic mutation through spontaneous deamination of 5-methylcytosine and cytosine
-
-
?
uracil-mismatched double-stranded DNA + H2O
uracil + double-stranded DNA with abasic site
thymine DNA glycosylase may play a backup role to the more efficient general uracil DNA glycosylase
-
-
?
additional information
?
-
inactivation of TDG significantly increases resistance of human cancer cells towards 5-fluorouracil. Excision of DNA-incorporated 5-fluorouracil by TDG generates persistent DNA strand breaks, delays S-phase progression, and activates DNA damage signaling. The repair of 5-fluorouracilinduced DNA strand breaks is more efficient in the absence of TDG. Excision of 5-fluorouracil by TDG (but not by uracil DNA glycosylases (UNG2 and SMUG1)) prevents efficient downstream processing of the repair intermediate, thereby mediating DNA-directed cytotoxicity
-
-
?
additional information
?
-
-
inactivation of TDG significantly increases resistance of human cancer cells towards 5-fluorouracil. Excision of DNA-incorporated 5-fluorouracil by TDG generates persistent DNA strand breaks, delays S-phase progression, and activates DNA damage signaling. The repair of 5-fluorouracilinduced DNA strand breaks is more efficient in the absence of TDG. Excision of 5-fluorouracil by TDG (but not by uracil DNA glycosylases (UNG2 and SMUG1)) prevents efficient downstream processing of the repair intermediate, thereby mediating DNA-directed cytotoxicity
-
-
?
additional information
?
-
uncertainty about the biological function of TDG. TDG is a DNA glycosylase involved in the repair of damaged DNA bases. Judged from its interactions with other proteins, it is a co-regulator of gene expression
-
-
?
additional information
?
-
-
TDG has a strong preference for uracil over thymine. TDG is an intriguing protein that, similar to SMUG1, has a low turnover number and strong binding to AP sites. The binding of the glycosylase to the AP site inhibits cleavage by the downstream AP endonuclease
-
-
?
additional information
?
-